rs267606670

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PM5PP2PP3_ModeratePP5_Very_Strong

The NM_152296.5(ATP1A3):​c.2767G>T​(p.Asp923Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D923N) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

ATP1A3
NM_152296.5 missense

Scores

15
3
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 7.91
Variant links:
Genes affected
ATP1A3 (HGNC:801): (ATPase Na+/K+ transporting subunit alpha 3) The protein encoded by this gene belongs to the family of P-type cation transport ATPases, and to the subfamily of Na+/K+ -ATPases. Na+/K+ -ATPase is an integral membrane protein responsible for establishing and maintaining the electrochemical gradients of Na and K ions across the plasma membrane. These gradients are essential for osmoregulation, for sodium-coupled transport of a variety of organic and inorganic molecules, and for electrical excitability of nerve and muscle. This enzyme is composed of two subunits, a large catalytic subunit (alpha) and a smaller glycoprotein subunit (beta). The catalytic subunit of Na+/K+ -ATPase is encoded by multiple genes. This gene encodes an alpha 3 subunit. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2012]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 17 ACMG points.

PM1
In a transmembrane_region Helical (size 19) in uniprot entity AT1A3_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_152296.5
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr19-41968837-C-T is described in Lovd as [Pathogenic].
PP2
Missense variant in the ATP1A3 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 110 curated pathogenic missense variants (we use a threshold of 10). The gene has 22 curated benign missense variants. Gene score misZ: 6.3327 (above the threshold of 3.09). Trascript score misZ: 9.1232 (above the threshold of 3.09). GenCC associations: The gene is linked to dystonia 12, alternating hemiplegia of childhood 2, ATP1A3-associated neurological disorder, developmental and epileptic encephalopathy 99, alternating hemiplegia of childhood, cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome, alternating hemiplegia of childhood 1, encephalopathy, acute, infection-induced.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.925
PP5
Variant 19-41968837-C-A is Pathogenic according to our data. Variant chr19-41968837-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 161148.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-41968837-C-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ATP1A3NM_152296.5 linkc.2767G>T p.Asp923Tyr missense_variant Exon 20 of 23 ENST00000648268.1 NP_689509.1 P13637-1Q53ES0
ATP1A3NM_001256214.2 linkc.2806G>T p.Asp936Tyr missense_variant Exon 20 of 23 NP_001243143.1 P13637-3Q53ES0
ATP1A3NM_001256213.2 linkc.2800G>T p.Asp934Tyr missense_variant Exon 20 of 23 NP_001243142.1 P13637-2Q53ES0
ATP1A3XM_047438862.1 linkc.2677G>T p.Asp893Tyr missense_variant Exon 20 of 23 XP_047294818.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ATP1A3ENST00000648268.1 linkc.2767G>T p.Asp923Tyr missense_variant Exon 20 of 23 NM_152296.5 ENSP00000498113.1 P13637-1
ENSG00000285505ENST00000644613.1 linkn.2767G>T non_coding_transcript_exon_variant Exon 20 of 25 ENSP00000494711.1 A0A2R8YEY8

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Alternating hemiplegia of childhood 2 Pathogenic:1
Sep 01, 2012
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Dystonia 12 Pathogenic:1
Aug 27, 2021
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This sequence change replaces aspartic acid with tyrosine at codon 923 of the ATP1A3 protein (p.Asp923Tyr). The aspartic acid residue is moderately conserved and there is a large physicochemical difference between aspartic acid and tyrosine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with alternating hemiplegia of childhood (PMID: 22850527, 24842602). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 161148). This variant disrupts the p.Asp923 amino acid residue in ATP1A3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19652145, 20576601, 23483595, 24123283). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1
Apr 28, 2017
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The D923Y variant in the ATP1A3 gene has been reported previously as a de novo change in an individual with alternating hemiplegia of childhood (Rosewich et al., 2012). In addition, a missense variant at the same residue (D923N) has been reported in association with ATP1A3-related disorders (Anselm et al., 2009; Brashear et al., 2012; Roubergue et al., 2013; Sasaki et al., 2014). The D923Y variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The D923Y variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret D923Y as a pathogenic variant -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.56
D
BayesDel_noAF
Pathogenic
0.56
CADD
Pathogenic
28
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.88
D;D;D;.;.
Eigen
Pathogenic
0.76
Eigen_PC
Uncertain
0.56
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
0.98
.;D;D;D;D
M_CAP
Pathogenic
0.81
D
MetaRNN
Pathogenic
0.92
D;D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
4.0
H;H;.;.;.
PrimateAI
Pathogenic
0.85
D
PROVEAN
Pathogenic
-6.0
.;D;.;D;D
REVEL
Pathogenic
0.91
Sift
Pathogenic
0.0
.;D;.;D;D
Sift4G
Uncertain
0.0030
.;D;D;D;D
Polyphen
1.0
D;D;.;.;.
Vest4
0.84, 0.86, 0.84
MutPred
0.65
Gain of MoRF binding (P = 0.0678);Gain of MoRF binding (P = 0.0678);.;.;.;
MVP
0.99
MPC
2.8
ClinPred
1.0
D
GERP RS
3.4
Varity_R
0.96
gMVP
0.98

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.060
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs267606670; hg19: chr19-42472989; API